tbuckley/cabot-search huggingface dataset:
Cabozantinib versus placebo in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on histology subtypes.
Authors: Jaume Capdevila, Bruce Robinson, Steven I. Sherman, Barbara Jarząb, Chia-Chi Lin, Fernanda Vaisman, Ana Hoff, Erika Hitre, Daniel W. Bowles, Denise Williamson, Jennifer Wright Oliver, Bhumsuk Keam, Marcia S. Brose
Journal: Journal of Clinical Oncology (2022)

6081 Background: DTC comprises multiple histology subtypes, the most common being papillary and follicular. Based on results of the phase 3 COSMIC-311 trial, the multikinase inhibitor cabozantinib was recently approved by FDA for the treatment of pts with RAIR DTC who progressed after prior VEGFR-targeted therapy (Brose et al. 2021). In an extended follow-up, median (m) progression-free survival (PFS) was 11 months (mo) for cabozantinib vs 1.9 mo for placebo (HR 0.22, 96% CI 0.15–0.32, P&lt;.0001) in the intent-to-treat (ITT) population (Capdevila et al. ESMO 2021. Abstr LBA67). Here we present outcomes for prespecified subgroups based on the baseline histology subtypes of papillary and follicular thyroid cancers. Methods: Pts were randomized 2:1 to cabozantinib (60 mg QD) or placebo. Placebo pts could cross over to open-label cabozantinib upon disease progression per blinded independent radiology committee (BIRC). Primary endpoints were PFS (ITT) and objective response rate (ORR, first 100 randomized pts), per RECIST v1.1 assessed by BIRC. Results: After a median follow-up of 10.1 mo, 258 pts (170 cabozantinib, 88 placebo) had been randomized (data cutoff 8 Feb 2021); 150 pts (96 cabozantinib, 54 placebo) had papillary thyroid cancer (PTC) and 113 pts (78 cabozantinib, 35 placebo) had follicular thyroid cancer (FTC), with the PTC and FTC subgroups each including 5 pts with both PTC and FTC. Sixty-three pts (̃56%) within the FTC subgroup had Hurthle cell and poorly differentiated variants. mPFS was 9.2 mo for cabozantinib vs 1.9 mo for placebo in the PTC subgroup (HR 0.27, 95% CI 0.17–0.43) and 11.2 mo vs 2.6 mo in the FTC subgroup (HR 0.18, 95% CI 0.10–0.31). The mPFS was 11.1 mo for cabozantinib and 1.9 mo for placebo for pts with Hurthle cell and poorly differentiated variants (HR 0.12, 95% CI 0.05–0.27). The ORR was 15% for cabozantinib vs 0% for placebo in the PTC subgroup and 8% vs 0% in the FTC subgroup. Median duration of cabozantinib exposure was 5.5 mo for the PTC subgroup and 7.3 mo for FTC. Grade 3/4 treatment-emergent adverse events (TEAE) in the cabozantinib arm occurred in 59% of pts in the PTC subgroup and 68% of pts in the FTC subgroup; discontinuations due to TEAE occurred in 17% and 15% of pts, respectively. Conclusions: In the extended follow-up, cabozantinib maintained superior efficacy vs placebo irrespective of histology subtype, including the aggressive Hurthle cell and poorly differentiated variants. The moderately higher rates of grade 3/4 TEAE in the FTC vs the PTC subgroup could be attributed to the longer median duration of exposure of cabozantinib in the FTC subgroup. Clinical trial information: NCT03690388.
Neoadjuvant chemotherapy plus tislelizumab followed by concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A single-arm, phase II trial.
Authors: Qiu-Yan Chen, Hai-Qiang Mai, Lin-Quan Tang, Meijuan Luo, Chong Zhao, Hao-Yuan Mo, Rui Sun, Dong-Hua Luo, Lin Wang, Shan-Shan Guo, Siyi Xie, Su-Chen Li, Sai-Lan Liu, Xiao Yun Li, Jing-Yun Peng, Hui-Zhi Qiu, Xue-Song Sun, LiTing Liu
Journal: Journal of Clinical Oncology (2022)

6068 Background: Neoadjuvant treatment with gemcitabine plus cisplatin (GP) prior to concurrent chemoradiotherapy (CCRT) has favorable survival outcomes with acceptable toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (LANPC), 10% of whom achieved complete response (CR) after neoadjuvant treatment. Immune checkpoint blockade therapy plus GP regimen has been shown to improve the survival in recurrent or metastatic NPC. We investigated the efficacy and safety of neoadjuvant treatment with GP plus tislelizumab, an anti-PD-1 monoclonal antibody, in previously untreated LANPC. Methods: In this phase II, single-armed Simon two-stage study, eligible patients are of age 18-70, with adequate haematological, renal, and hepatic function, diagnosed with staged III-IVa（AJCC 8 th ） non-keratinizing LANPC. Enrolled patients received intravenous gemcitabine (1000 mg/m2) on days 1 and 8, cisplatin (80 mg/m2) on day 1, and tislelizumab (200mg) on day 1 every 3 weeks for 3 cycles followed by standard CCRT. The primary endpoint was CR rate after neoadjuvant treatment, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator. The secondary endpoints included pathology complete response (pCR) rate, 2-year progress-free survival (PFS), overall survival (OS), locoregional failure-free survival (LRRFS), distant metastasis-free survival (DMFS), and toxicity. This study is registered with ClinicalTrials.gov, NCT04833257, all enrolled patients have finished their treatment and the follow-up is ongoing. Results: From April 14th 2021 to August 5th, 2021, a total of 63 patients (median age 46y, 74.6% male) were enrolled at Sun Yat-sen University Cancer Center. As of January 31st, 2022, the median follow-up is 7.37 months, no patients had disease progression. The CR rate after neoadjuvant treatment was 41.3% (95% CI, 28.8% to 53.8%). The ORR and pCR rate were 88.9% (95% CI, 80.9% to 96.9%) and 75.8% (95% CI, 64.8% to 86.8%), respectively. The incidence of acute treatment-related AEs (trAEs) and immune-related adverse events (irAEs) of grade 3 or 4 was 69.8% and 3.2%, respectively. All of irAEs for grade 3 or 4 were hepatotoxicity and skin rash. Long-term efficacy is awaited. Conclusions: Neoadjuvant treatment with GP plus tislelizumab achieved impressive CR rate and pCR rate with manageable toxicities. Further follow-up is needed to confirm the long-term efficacy. Clinical trial information: NCT04833257.
Efficacy and safety of selpercatinib in RET-altered tumors: A systematic review and meta-analysis.
Authors: Mina Choudhry, Iman Waheed Khan, Mukarram Jamat Jamat Ali, Mati Ullah Dad Ullah, Muhammad Yasir Anwar, Muhammad Ashar Ali, Wajeeha Aiman
Journal: Journal of Clinical Oncology (2022)

6091 Background: RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib was the first RET-specific tyrosine kinase inhibitor approved by FDA in RET-altered tumors (pralsetinib was approved afterward). This systematic review and meta-analysis will assess the efficacy and safety of selpercatinib in RET-altered tumors. Methods: A search was performed on PubMed, Embase, Cochrane, WOS, and clinicaltrials.gov. We used the following mesh and Emtree terms, “selpercatinib” AND “proto oncogene proteins c ret,” from the inception of literature till 10/15/2021. We screened 187 articles and included 2 phase I/II clinical trials (N = 309) in this meta-analysis. We excluded preclinical trials, case reports, case series, review articles, observational studies, meta-analysis, and clinical trials not providing any information about the efficacy of selpercatinib in RET-altered tumors. The quantitative analysis was performed using the R programming language. Results: In 2 clinical studies (N = 309), 144 patients had RET-altered advanced non-small cell lung cancer (NSCLC) and 162 had thyroid cancer. RET mutations were reported in 143 patients and RET-fusion in 163 tumors. 179 patients were previously treated with systemic therapy while 127 patients were treatment naïve. Pooled overall response (OR), complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) were 72% (95% CI = 0.64-0.78, I 2 = 40%), 6% (95% CI = 0.03-0.13, I 2 = 49%), 66% (95% CI = 0.57-0.74, I 2 = 50%), 3% (95% CI = 0.01-0.06, I 2 = 0), and 24% (95% CI = 0.18-0.30, I 2 = 22%), respectively, in RET-altered thyroid/NSCLC patients. Pooled OR was 67% (95% CI = 0.60-0.73, I 2 = 0), 78% (95% CI = 0.64-0.87, I 2 = 51%), 75% (95% CI = 0.58-0.87, I 2 = 68%), and 71% (95% CI = 0.63-0.78, I 2 = 0%) in previously treated, treatment naïve, RET-fusion tumor, and RET-mutation tumor patients, respectively. Pooled incidence of ≥grade 3 any adverse event, rise in ALT, rise in AST, diarrhea, hypertension, and QT abnormalities were reported in 58% (95% CI = 0.43-0.72, I 2 = 85%), 10% (95% CI = 0.08-0.14, I 2 = 0), 11% (95% CI = 0.07-0.15, I 2 = 17), 5% (95% CI = 0.03-0.08, I 2 = 0), 17% (95% CI = 0.11-0.26, I 2 = 62%), and 4% (95% CI = 0.02-0.07, I 2 = 18%) of the participants, respectively. Conclusions: Selpercatinib was safe and effective in patients with RET-altered NSCLC and thyroid cancer regardless of prior treatment status and type of RET alteration. On indirect comparison, the safety profile with selpercatinib was better than previously used non-specific RET-inhibitors. Randomized clinical trials (RCTs) NCT04211337 and NCT04194944 are in progress to compare selpercatinib with non-specific RET inhibitors and chemotherapy/PD-1 inhibitor. More RCTs are needed to assess the combinations of selpercatinib with other drugs.
The mutational landscape of medullary thyroid carcinoma using whole-exome sequencing in China.
Authors: Chen Huang, Jinxi Di, Ruiying Jiang, Xiaowei Wang, Ye Wang, Qianqian Feng, Siyao Liu, Yun Niu, Yanfen Shi, Jie Lin, Bei Wang, Jie Luo, Dingrong Zhong, Jie Tong
Journal: Journal of Clinical Oncology (2022)

6054 Background: Medullary thyroid carcinoma (MTC) is a rare malignancy, and its molecular pathogenesis is far from being understood. Therefore, a relatively comprehensive and accurate genomic profiling is needed for the future molecular diagnosis, treatment and early prevention of MTC patients. Methods: In this study, we investigated both the somatic and germline mutational spectrum of MTC, whole-exome sequencing (WES) was performed on tumor samples and matched noncancerous tissues from 30 MTC patients. Genetic alterations were defined and analyzed using MutSigCV and novel germline mutations were identified using MutationTaster and cross-referenced in PubMed. Results: In somatic mutational spectrum we found the top three significantly mutated genes (SMGs) in our MTC samples were RET, FAM186A and PRG4 genes (33%, 33% and 27%, respectively). For the germline mutations, FAT4 was detected as the most common mutated genes, following by RET and FAT1. Besides, we identified 30 novel germline mutations such as IGF1R, PDK1, NOTCH1, RPTOR, MPL, SETD2 and ARID2. Those mutated genes have been previously associated with neurofibromatosis, Lynch syndrome and other diseases respectively and now predicted potential functional pathogenicity in the patients with MTC. Conclusions: The study elucidated a relatively more comprehensive genomic landscape of MTC. In addition to the RET gene, which has been studied extensively, other SMGs may also be of interest including novel germline mutations. These findings may indicate the potential basis of molecular diagnosis, early prevention and targeted therapeutic options for patients with MTC in the future.
Transoral robotic surgery (TORS)-guided radiotherapy (RT) volume de-intensification in p16-positive unknown primary squamous cell carcinoma (SCC) of the neck: A phase 2 trial (FIND).
Authors: John R de Almeida, David Paul Goldstein, Rosemary Martino, Jie Su, Ali Hosni, Scott Victor Bratman, Douglas Brian Chepeha, John Waldron, Ilan Weinreb, Bayardo Perez-Ordonez, Eugene Yu, Ur Metser, Aaron Richard Hansen, Wei Xu, John Kim
Journal: Journal of Clinical Oncology (2022)

6067 Background: TORS has improved the likelihood of identifying an oropharyngeal cancer for patients presenting with unknown primary. We evaluate the oncologic and functional outcomes after reduction of RT volumes based on TORS findings. Methods: Patients with p16-positive, neck SCC (cN1-N3) with no primary on examination and CT/MRI were included between 08/2017 and 12/2019. All patients underwent PET-CT, surgical evaluation with either therapeutic intent including neck dissection for cN1 without extranodal extension (Group 1, n=9) or diagnostic intent (Group 2, n=13). Patients underwent excision of palatine tonsil (PT) followed by lingual tonsil (LT), if the PT was negative, or excision of PET-CT avid regions. Pharyngeal-sparing radiotherapy (PSRT) was given when no primary was found (pT0) and for primaries completely excised (margins &gt;= 3mm). Unilateral neck radiotherapy (UNRT) was given for lateralized (&gt;1 cm from midline) primaries or pT0 with unilateral disease. The primary outcome was 2-year out-of-treated volume failures (OTVF). Swallowing-related quality of life (SR-QOL) was measured using MD Anderson Dysphagia Inventory (MDADI) composite score. A sample size of 22 was required assuming OTVF cannot exceed 15% (vs. 1% historical), power of 0.8, alpha of 0.05 (one-sided), and loss to follow-up of 10%. Results: All 22 patients [median age 60 (46-68); 86% male; 86% N1, 9% N2, 5% N3] underwent surgical evaluation. PET-CT showed suspicious findings in 12 (55%) [sensitivity = 0.44, specificity = 0.29]. Excision of PT and LT were performed in 14 (64%) and 14 (64%) patients respectively; and 8 (36%) had previous PT. Oropharyngeal primaries were found in 17 patients (77%) [14 (64%) single primary, 3 (13%) two primaries]. RT volume de-intensification was achieved in 11 patients (50%) who had PSRT and 10 (45%) who had UNRT. In Group 1, adjuvant RT was given to 6 (67%) and CRT to 1 (11%). In group 2, 8 (62%) had RT and 5 (38%) had CRT. There were no OTVF, local, or regional failures [median follow-up 29 months]. Two-year OS, DFS, and LRC were 100%, 95%, and 100%. SR-QOL showed good recovery (Table). Grade III/IV surgical as well as acute and late toxicities occurred in 2 (9%), 5 (23%), and 1 (5%) respectively. Conclusions: TORS evaluation for p16-positive unknown primary SCC allowed RT volume de-intensification with excellent disease control and quality of life. Future randomized trials can compare transoral surgery versus existing diagnostic approaches. MDADI composite scores. Clinical trial information: NCT03281499. [Table: see text]
A Standardized and Regionalized Network of Care for Cardiogenic Shock
Authors: Behnam N. Tehrani, Matthew W. Sherwood, Carolyn Rosner, Alexander G. Truesdell, Seiyon Ben Lee, Abdulla A. Damluji, Mehul Desai, Shashank Desai, Kelly C. Epps, Michael C. Flanagan, Edward Howard, Nasrien Ibrahim, Jamie Kennedy, Hala Moukhachen, Mitchell Psotka, Anika Raja, Ibrahim Saeed, Palak Shah, Ramesh Singh, Shashank S. Sinha, Daniel Tang, Timothy Welch, Karl Young, Christopher R. deFilippi, Alan Speir, Christopher M. O’Connor, Wayne B. Batchelor
Journal: JACC Heart Failure (2022)
Sublingual Boosting with a Novel Mucoadhesive Thermogelling Hydrogel Following Parenteral CAF01 Priming as a Strategy Against <i>Chlamydia trachomatis</i> (Adv. Healthcare Mater. 11/2022)
Authors: Lorena Garcia‐del Rio, Patricia Diaz‐Rodriguez, Gabriel Kristian Pedersen, Dennis Christensen, Mariana Landin
Journal: Advanced Healthcare Materials (2022)

Sublingual Vaccines In article number 2102508 by Mariana Landin and co-workers, an optimized hydrogel is developed using artificial intelligence for sublingual delivery of the Chlamydia subunit vaccine CTH522, following parenteral immunization with this vaccine included in CAF01 liposomes. This strategy promotes Th1&Th17 immune responses and elicits a local IgA response in the genital tract. Cover made by Leticia Goimil García.
Physical activity and risk of infection, severity and mortality of COVID-19: a systematic review and non-linear dose–response meta-analysis of data from 1 853 610 adults
Authors: Yasmin Ezzatvar, Robinson Ramírez-Vélez, Mikel Izquierdo, Antonio Garcia-Hermoso
Journal: British Journal of Sports Medicine (2022)

Objective To quantify the association between physical activity and risk of SARS-CoV-2 infection, COVID-19-associated hospitalisation, severe illness and death due to COVID-19 in adults. Design A systematic review and meta-analysis. Data sources Three databases were systematically searched through March 2022. Eligibility criteria for selecting studies Peer-reviewed articles reporting the association between regular physical activity and at least one COVID-19 outcome in adults were included. Risk estimates (ORs, relative risk (RR) ratios or HRs) were extracted and pooled using a random-effects inverse-variance model. Results Sixteen studies were included (n=1 853 610). Overall, those who engaged in regular physical activity had a lower risk of infection (RR=0.89; 95% CI 0.84 to 0.95; I 2 =0%), hospitalisation (RR=0.64; 95% CI 0.54 to 0.76; I 2 =48.01%), severe COVID-19 illness (RR=0.66; 95% CI 0.58 to 0.77; I 2 =50.93%) and COVID-19-related death (RR=0.57; 95% CI 0.46 to 0.71; I 2 =26.63%) as compared with their inactive peers. The results indicated a non-linear dose–response relationship between physical activity presented in metabolic equivalent of task (MET)-min per week and severe COVID-19 illness and death (p for non-linearity &lt;0.001) with a flattening of the dose–response curve at around 500 MET-min per week. Conclusions Regular physical activity seems to be related to a lower likelihood of adverse COVID-19 outcomes. Our findings highlight the protective effects of engaging in sufficient physical activity as a public health strategy, with potential benefits to reduce the risk of severe COVID-19. Given the heterogeneity and risk of publication bias, further studies with standardised methodology and outcome reporting are now needed. PROSPERO registration number CRD42022313629.
Phase 3 randomised study evaluating the addition of low-dose nivolumab to palliative chemotherapy in head and neck cancer.
Authors: Vijay Maruti Patil, Vanita Noronha, Nandini Sharrel Menon, Atanu Bhattacharjee, Suman Kumar, Nilendu Purandare, Archi Agrawal, Ameya Puranik, Kavita Prakash Nawale, Shweta Jogdhankar, Mitali Alone, Rupali Tambe, Riddhi Sawant, Devanshi Kalra, Sachin Babanrao Dhumal, Shripad Dinanath Banavali, Kumar Prabhash
Journal: Journal of Clinical Oncology (2022)

LBA6016 Background: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma (HNSCC) are accessible to only 1-3% of patients in low and middle-income countries due to cost. In our previous study, metronomic chemotherapy (MC) improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low dose nivolumab to MC improved the overall survival. Methods: This was a randomised phase 3 superiority open-label study. Adult patients with relapsed -recurrent or newly diagnosed advanced HNSCC being treated with palliative intent with ECOG PS 0-1 were eligible. Patients were randomised 1:1 to MC consisting of methotrexate 15 mg/m2 PO weekly, celecoxib 200 mg PO daily and erlotinib 150 mg PO daily, or MC with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Therapy was continued until disease progression or intolerable adverse events. Response assessment (RECIST version 1.1) was performed every 2 months. The primary endpoint was 1-year overall survival (OS) and this was a pre-specified interim analysis with the nominal p-value for efficacy being 0.006. Results: 151 patients were randomised, 75 in MC and 76 in the MC-I arm respectively. The addition of low dose nivolumab led to an improvement in the 1-year overall survival from 16.3% (95%CI 7.95-27.4) to 43.4% (95% CI 30.8-52.3) [Hazard ratio-0.545; 95%CI 0.362-0.82; P=0.00358]. The median overall survival in MC and MC-I arms was 6.7 months (95%CI 5.83 -8.07) and 10.1 months (95%CI 7.37-12.63) respectively (P=0.0052). The median progression-free survival in MC and MC-I arms was 4.57 months (95%CI 4.2 -5.3) and 6.57 months (95%CI 4.43-8.9) respectively (P=0.0021). Response rate in MC and MC-I arm were 49.3% (95% CI 37.8-60.8) and 65.2% (95%CI 53.4-75.4) respectively (P=0.085). The rate of grade 3 and above adverse events was 50% and 46.1% in MC and MC-I arm respectively (P=0.744). Conclusions: In this first-ever randomised study, the addition of low dose nivolumab led to improved overall survival and is an alternative standard of care for those who cannot access full dose nivolumab. Clinical trial information: CTRI/2020/11/028953.
Results of phase 3 randomized trial for use of docetaxel as a radiosensitizer in patients with head and neck cancer unsuitable for cisplatin-based chemoradiation.
Authors: Vijay Maruti Patil, Vanita Noronha, Nandini Sharrel Menon, Sarbani Laskar, Ashwini Budrukkar, Monali Swain, Atanu Bhattacharjee, Arun Balaji, Pankaj Chaturvedi, Devendra A Chaukar, P. S. Pai, Sudhir Vasudevan Nair, Nilendu Purandare, Archi Agrawal, Ameya Puranik, Kavita Prakash Nawale, Vijayalakshmi Mathrudev, Kumar Prabhash
Journal: Journal of Clinical Oncology (2022)

LBA6003 Background: Systemic therapy options have not been systematically evaluated in cisplatin-ineligible locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients undergoing chemoradiation. This study evaluated docetaxel as a radiosensitizer in this setting. Methods: This was a randomised open-label study. Adults with LAHNSCC planned for radical or adjuvant chemoradiation, with ECOG PS 0-2 and who were cisplatin-ineligible as per the criteria by Ahn et al were enrolled. The patients were randomly assigned 1:1 to receive radiation alone or radiation with concurrent docetaxel 15 mg/m 2 weekly for a maximum of 7 cycles. Adverse events were recorded in accordance with CTCAE version 4.03. The FACT-G, and H and N questionnaires (version 4) were self-administered at baseline, 6 months, 12 months and at 24 months. The primary endpoint was disease-free survival (DFS) and key secondary endpoints were overall survival (OS), adverse events and quality of life (Trial outcome index (TOI)). Results: The study recruited 356 patients with 176 in RT and 180 in the docetaxel-RT arm. The 2-year DFS was 30.3% (95%CI 23.6-37.4) versus 42% (95%CI 34.6-49.2) in the RT and docetaxel-RT arms respectively (Hazard ratio- 0.673; 95% CI 0.521-0.868; P-value=0.002). The median overall survival (OS) was 15.3 months (95%CI 13.1-22) in the RT arm and 25.5 months (95% CI 17.6-32.5) in the docetaxel-RT arm. (Log-rank P-value =.0.035). The 2 -year OS was 41.7% (95%CI 34.1-49.1) versus 50.8% (95%CI 43.1-58.1) in the RT and docetaxel-RT arms respectively (Hazard ratio-0.747; 95% CI 0.569-0.98; P-value=0.035). Any grade 3 or above adverse events were seen in 102 patients (58%) in RT and in 146 (81.6%) in docetaxel-RT arms respectively (P-value=0.000). There was a higher incidence of grade 3 and above mucositis (22.2% versus 49.7%; P&lt;0.001), odynophagia (33.5% versus 52.5%; P&lt;0.001) and dysphagia (33% versus 49.7%; P&lt;0.002) with the addition of docetaxel. The addition of docetaxel did not lead to a worsening of TOI scores and FACT-G scores at 6 months. Conclusions: The addition of docetaxel to radiation improved disease-free survival and overall survival in cisplatin-ineligible LAHNSCC and represents a new standard of care. Clinical trial information: CTRI/2017/05/008700.